Factors Affecting Carotid Artery Stenosis in the Elderly Living at High Altitudes

Background: Factors affecting carotid artery stenosis have been generally investigated. However, considering the protective effect of altitude, studies on elderly individuals at high altitudes are few. Our aim is to investigate the systematic adaptive changes caused by high-altitude exposure through the causes of carotid artery stenosis. Materials and methods: Carotid Doppler ultrasound was performed on 250 patients over the age of 50 years. The patients' age, gender, height, weight, smoking history, place of residence, and presence of comorbidities were questioned. Those with diabetes, hypertension, hyperlipidemia, and coronary disease were excluded from the study. Those who did not reside at high altitudes were excluded from the study. One hundred and thirty-five patients were included in the study. Carotid artery Doppler findings and biochemical parameters were recorded. Factors affecting stenosis in the carotid arteries were compared. Results: In our study, the factors affecting carotid stenosis were determined to be age, gender, presence of plaque, plaque type, and mean carotid intima-media thickness (CIMT). The mean CIMT of the patients was calculated as 0.71±0.14 mm. The mean CIMT measurement level was significantly higher in patients with plaque in the carotid artery (p<0.05). According to receiver operating characteristic curves, CIMT values higher than 0.72 mm increase plaque and stenosis formation in the common carotid artery (CCA) and internal carotid artery (ICA) in elderly people living at high altitudes (p<0.05, area under the curve [AUC]: 0.71-0.83). Conclusions: The most important factors affecting carotid stenosis in individuals living at high altitudes are age, gender, CIMT, plaque, and plaque type. When soft plaques were detected, the risk of stenosis was found to be higher than in calcific plaques. Additionally, the number of factors affecting stenosis was greater on the left (ICA). This suggests that the left carotid system is more vulnerable. It can be said that in elderly individuals living at high altitudes, a CIMT higher than 0.72 mm is a cutoff value in the presence of plaque and stenosis in the carotid arteries.


Introduction
Endothelial function at high altitudes has only been measured in populations genetically adapted to chronic hypoxia.At high altitudes, endothelial dysfunction was higher in genetically unadapted individuals and in individuals with risk factors such as diabetes, obesity, and hypertension.The vasodilatory response of arteries was found to be better in those living at high altitudes [1].The hypoxic conditions caused by high altitude are believed to provide a protective effect against cardiovascular and metabolic diseases compared to those living at sea level.However, in the case of chronic hypoxia at high altitude, the chronic mountain disease known as hypererythrocytosis, cardiovascular risk was reported to be 3.63 times higher in individuals with cardiovascular disease than in normal individuals [2].In the Tibetan migrant population living in highaltitude areas, women were found to have a higher prevalence of obesity and metabolic syndrome than men.There was also no association between diabetes and obesity [3].It has been emphasized that hypoxemia at high altitudes is also evident in high body mass index (BMI), older age, male gender, and especially in the winter months [4].The effect of altitude on hypertension was investigated in three populations living at different altitudes in Tibet.Among 1631 participants, the prevalence of hypertension decreased with increasing altitude in individuals living at low, medium, and high altitudes.It was 40.6% at low altitude, 32.5% at medium altitude, and 20.4% at high altitude.Increasing altitude decreased BMI, and thus the prevalence of hypertension decreased [5].Those living at high altitudes had higher muscle density in the gluteus maximus and L2 trunk muscles compared to sea level, suggesting that living at a higher altitude may be beneficial for muscle quality [6].Obesity and metabolic syndrome are risk factors for cardiovascular diseases.In a study of 10,318 participants, participants were divided into three different altitude groups: those living at altitudes lower than 500 meters, between 500 and 1500 meters, and those living at altitudes

Statistical analyses
Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS) version 25.0 (IBM Corp, Armonk, NY) program.The conformity of the variables to a normal distribution was examined by the Shapiro-Wilk test.Mean, standard deviation, median, minimum, and maximum values were used for descriptive analyses.The Mann-Whitney U test was used to evaluate variables that did not show a normal distribution between the two groups.Frequency and percentage values of the variables were used when presenting categorical variables.The relationships between categorical variables were analyzed by the Fisher-Freeman-Halton exact test.Differences between groups were determined by the Dunn-Bonferroni test.Receiver operating characteristic (ROC) analysis was performed to determine a threshold value for the discriminability of the mean CIMT measurement in the prediction of stenosis and plaque.When determining the threshold value, the cutoff point with the highest sensitivity and selectivity was taken.The area under the curve is interpreted as having excellent discrimination power between 1.0 and 0.90, good between 0.90 and 0.80, fair between 0.80 and 0.70, poor between 0.70 and 0.60, and almost no discriminatory power between 0.60 and 0.50.Multiple logistic regression analyses were performed to determine the independent variables affecting the stenosis-dependent variable.p-Values below 0.05 were considered statistically significant results.

Results
A total of 135 patients were included in the study to determine the factors that most affect carotid stenosis in elderly patients at high altitudes.60.74% of the patients were female, with a mean age of 66.78±9.65 years.23.7% of the patients were smokers, and 21.5% of the patients had the right CCA plaque, 15.6% had right ICA plaque, 24.4% had the left CCA plaque, and 19.2% had the left ICA plaque.Right CCA stenosis was found in 5.9%, right ICA stenosis in 7.4%, left CCA stenosis in 9.6%, and left ICA stenosis in 9.6% of the patients.The mean right IMT measurement was 0.71±0.13mm, and the mean left IMT measurement was 0.73±0.14mm.Other clinical descriptive statistics of the patients are given in Table 1.There was no significant relationship between right CCA stenosis and demographic variables (p>0.05).The rates of CCA plaque, CCA plaque type, and ICA stenosis were significantly higher in patients with right CCA stenosis (p<0.05).In addition, the mean CIMT measurement level in patients with right CCA stenosis (M=0.8) was significantly higher than in patients without stenosis (M=0.7)(p=0.033)(Tables 2, 3).The age of patients with right ICA stenosis (M=74.5)was higher than that of patients without stenosis (M=65) (p=0.010).The rates of CCA plaque, ICA plaque, and ICA plaque type were significantly higher in patients with right ICA stenosis (p<0.05).In addition, right IMT and mean CIMT measurement levels were significantly higher in patients with right ICA stenosis than in patients without stenosis (p=0.042 and p=0.024, respectively).The TG measurement level was lower in patients with right ICA stenosis than in patients without stenosis (p=0.038)(Tables 4, 5).The age of patients with left CCA stenosis (M=74) was higher than that of patients without stenosis (M=65) (p=0.048).The rates of CCA plaque, CCA plaque type, and ICA stenosis were significantly higher in patients with left CCA stenosis (p<0.05).In addition, patients with left CCA stenosis had significantly higher left IMT, left ICA stenosis (%), and mean CIMT measurements than patients without stenosis (p<0.05)(Tables 6, 7).The age of the patients with left ICA stenosis (M=76) was higher than that of the patients without ICA stenosis (M=65) (p=0.001).The rates of CCA plaque, CCA plaque type, ICA plaque, and ICA plaque type were significantly higher in patients with left ICA stenosis (p<0.05).In addition, left IMT and mean CIMT measurements were significantly higher in patients with left ICA stenosis than in patients without stenosis (p<0.05)(Table 8).However, HDL measurement level was lower in patients with left ICA stenosis compared to patients without stenosis (p=0.035)(Table 9).The mean CIMT measurement level was significantly higher in patients with plaque (p<0.05)(Table 10).We aimed to determine a threshold value for the discriminability of the mean CIMT measurement in the prediction of CCA and ICA stenosis.Here, a high mean CIMT measurement indicates that the patient has stenosis.Accordingly, the cutoff point with the highest sensitivity and selectivity for the mean CIMT measurement in right CCA stenosis is 0.725 mm.When people with a mean CIMT value above 0.725 mm are diagnosed with right CCA stenosis, the sensitivity of the mean CIMT value is 75% and the selectivity is 61.4%.The area under the ROC curve is 72.5%.Accordingly, it can be said that the discriminative power of the mean CIMT variable is moderate.The 95% confidence interval for this area was obtained as 58%-87%.The obtained area value was found to be statistically significant (p=0.033).The mean CIMT threshold values for the other stenosis variables are also shown in Table 11.In patients with right-left CCA and ICA stenosis, the proportion of males (57.69%) was higher and the proportion of females (42.31%) was lower (p=0.032).The rates of CCA plaque, CCA plaque type, ICA plaque, and ICA plaque type were also significantly higher in patients with stenosis (p<0.001)(Table 12).Age measurement was higher in patients with stenosis (p=0.001).In addition, the mean CIMT measurement level (M=0.8) was higher in patients with stenosis than in patients without stenosis (p<0.001)(Table 13).

Discussion
In our study investigating the factors affecting carotid stenosis in elderly patients at high altitudes, factors were evaluated bilaterally for CCA and ICA.We found that the factors affecting stenosis were associated with gender, age, plaque, plaque type, duration of high altitude, and mean IMT thickness.We also determined the mean CIMT cutoff value affecting plaque formation for bilateral CCA and ICA in individuals living at high altitudes.The risk of significant stenosis in CCA and ICA differed significantly according to plaque type.
A study in a Peruvian population living at high altitudes found a significant and negative association with the Framingham 10-year risk score in individuals living above 2500 meters, with lower mean systolic blood pressure and lower diagnoses of diabetes compared to those residing at lower altitudes [9].In a study investigating the effects of smoking and altitude on blood 25-hydroxy vitamin D, testosterone, and carotid artery thickness, smoking significantly increased the intima-media thickness of the right and left carotid arteries at both high and low altitudes (p≤0.001).Smoking at high altitudes was reported to be associated with a significant increase in 25-hydroxy vitamin D and testosterone concentrations, whereas at low altitudes it was associated with a significant decrease in both parameters.It was emphasized that changes in these biochemical parameters should be kept in mind in the dose modification of drugs when treating patients [10].In our study, since the altitude was kept constant, the effect of biochemical parameters on carotid stenosis was not found in individuals living at high altitudes.Although the mean number of cigarette pack-years smoked was higher in individuals with significant carotid stenosis in our study, no statistical difference was found.However, mean IMT values were significantly higher, indicating that cigarette smoking affects IMT.
Carotid atherosclerosis is a risk factor for ischemic stroke.Detection of plaques, stenosis, and IMT on carotid Doppler ultrasound can prevent further strokes.In ischemic stroke cases, IMT was found to be 0.79±0.10mm on the right side and 0.90±0.17mm on the left, and CIMT was found to be significantly higher in the case group than in the control group [11].In our study, the mean CIMT thickness was found to be significantly higher in individuals with significant stenosis in the CCA and ICA (0.82±0.13).In individuals living at high altitudes, the average IMT thickness being higher than 0.725 mm was found to be a significant cutoff value for the development of plaque and stenosis in ICA and CCA.
CIMT values have been researched for many diseases in the literature.The average was found to be 0.91 mm in lacunar infarcts and 1.04 mm in non-lacunar infarcts [12].In ischemic strokes, large vessel and small vessel disease differ in terms of CIMT.CIMT values are significantly higher in large vessel involvement (1.08 mm) than in small vessel involvement (0.92 mm) [13].Diabetic patients were found to have increased CIMT values in parallel with more atherosclerotic changes compared to non-diabetic patients [14].In a cohort of middle-aged women, metabolic syndrome was found to be more strongly associated with atherosclerosis as determined by CIMT than by the International Diabetes Federation definition or other definitions of metabolic health, and more strongly than BMI or waist circumference [15].In our study, significant stenosis was compared with gender, age, and BMI.Age and gender were found to be important variables.In a systematic review and meta-analysis study including 16,179 cases and 26,120 control individuals, it was reported that a 0.12 mm increase in CIMT was associated with non-alcoholic liver disease [16].A systematic review investigating the global variation and demographic relationship of CIMT included 49,381 individuals with a mean age of 55.6 years.The average CIMT value for the group without coronary heart disease was found to be 0.65 and showed regional differences.CIMT in Europe was detected at 0.71 mm.CIMT was found to be 0.23 mm higher in the group with coronary heart disease.In this review, it was reported that CIMT increases with age, and the average is 0.76 in the 60-69 years age range.In our study, the median and mean age were 66, and the mean IMT was found to be 0.71±0.14 and 0.69±0.13 in individuals without stenosis, which is correlated with the study results [17].In a study investigating the characteristics of carotid plaques, the plaques, which were described as predominantly hypoechoic and soft plaques in our study, were found to be associated with cerebrovascular symptomatic individuals.Surface irregularity, plaque length, and area have been reported as other important variables of plaque morphology.However, no difference was detected between cerebrovascular symptomatic and non-symptomatic individuals in terms of plaque thickness and CIMT [18].Carotid artery atherosclerosis is distributed asymmetrically in the carotid vessels.
Plaques were more common on the left.Additionally, intraplaque bleeding and fibrous tissue were more commonly detected in the carotid plaques on the left side.It is emphasized that the plaques on the left are more vulnerable and the plaques on the right are more stable [19].In our study, it was determined that the area under the curve of the average CIMT value in the ROC curves used to detect plaque and stenosis was greater on the left.
The limitations of our study are that it was a retrospective, single-center study, and was evaluated in a limited number of patients.Furthermore, although diseases affecting carotid stenosis were excluded, there are no data on ethnicity, lifestyle, dietary habits, or exercise that may affect stenosis.

Conclusions
Consequently, all variables were analyzed separately for bilateral CCA and ICA.The most important variables in all patients were age, gender, CIMT, plaque in CCA and ICA, and plaque type.When soft plaques were detected, the risk of stenosis was found to be higher than in calcific plaques.Additionally, the number of factors affecting stenosis was greater in the left ICA.This suggests that the left carotid system is more vulnerable.The CIMT value was significantly higher in patients with plaque in the carotid artery.Our results show that CIMT values higher than 0.72 mm are associated with plaque and stenosis in the carotid arteries in elderly individuals living at high altitudes.

FIGURE 1 :
FIGURE 1: Intima-Media Thickness Measurements From Bilateral Common Carotid Artery

TABLE 11 : ROC Analysis of Mean CIMT Value in Predicting CCA and ICA Stenosis
ROC: receiver operating characteristic; CCA: common carotid artery, ICA: internal carotid artery; CIMT: carotid intima-media thickness.

TABLE 13 : Factors Causing Significant Stenosis in All Patients
regression model was created to estimate the significant effects of independent variables on the dependent variable of stenosis.Independent variables with p-value <0.20 in the single logistic regression model were included in the multiple logistic regression model.In the multiple logistic regression model, the best model was obtained by using the forward (LR) selection method (-2 Log likelihood = 64.043;NagelkerkeRsquare = 0.635; p<0.001).The model fit was adequate (Hosmer and Lemeshow test, p=0.753).In the estimated model, CCA plaque type and ICA plaque type independent variables contributed significantly to the model.The risk of stenosis in patients with plaque type soft was 47.7 times higher than in patients without plaque (p<0.001;95%CI(7.617-298.998)).The risk of stenosis in patients with plaque type Ca is 14.5 times higher than in patients without plaque (p=0.005;95%CI:7.232-94.421).The risk of stenosis in patients with ICA plaque type soft was 175.86 times higher than in patients without plaque (p<0.001;95%CI(15.27-2025.3)).The overall classification percentage of the estimated model was 88.9% (Table14). A